AbstractBackground/Aims
Interferon-based treatment is not appropriate for a large number of patients with chronic hepatitis C for various medical and social reasons. Newly developed directly acting antivirals (DAAs) have been used to treat chronic hepatitis C without severe adverse effects and have achieved a sustained viral response (SVR) rate of 80-90% with short treatment duration. We were interested to determine whether all patients who failed to respond to or were ineligible for interferon-based therapy could be treated with DAAs.

Methods
Medical records of patients with positive serum anti-hepatitis C virus (HCV) or HCV RNA between January 2009 and December 2013 were reviewed. Demographic, clinical, and treatment data were collected for analysis.

Results
A total of 876 patients were positive for both anti-HCV and HCV RNA. Of these, 244 patients were eligible for interferon, although this was associated with relapse in 39 (16%) of patients. In total, 130 patients stopped interferon therapy (67% adverse effects, 28% non-adherent, 4% malignancy, 1% alcohol abuse) and 502 patients were ineligible (66% medical contraindications, 25% non-adherent, 5% socioeconomic problems). Among 671 patients who were ineligible for or failed to respond to interferon therapy, more than 186 (27.7%) could not be treated with DAA due to financial, social, or cancer-related conditions.

Conclusions
Newly developed DAAs are a promising treatment for patients with chronic hepatitis C who are ineligible for or failed to respond to interferon-based therapy. Nevertheless, not all chronic hepatitis C patients can be treated with DAAs due to various reasons.

The prevalence of blood-borne HCV infection is estimated to be about 3% worldwide. Although DAAs that target nonstructural protein of HCV have potent antiviral efficacy and few adverse effects, the eradication of HCV is supposed to be difficult because most acute and chronic HCV infection is asymptomatic, and screening programs are limited in most countries. In a prospective, multicenter cohort at five university hospitals from January 2007 to December 2011, 1,173 patients age >18 years who were positive for anti-HCV antibody were enrolled to investigate the epidemiological and clinical characteristics of HCV infection of Korea. The rate of antiviral therapy for HCV was 42.8% of the HCV cohort [7]. At our center, 876 patients were diagnosed in a chronic viremic state, and 374 (42.6%) were treated with interferon-based therapy.

PegIFN-α and ribavirin combination therapy have absolute contraindications including uncontrolled depression; psychosis or epilepsy; pregnancy or couples unwilling to use adequate contraception; severe concurrent medical diseases; and co-morbidities including retinal disease, autoimmune thyroid disease, and decompensated liver disease [8]. After considering the contraindications for interferon-based therapy, a large number of patients diagnosed with chronic hepatitis C could not have treatment. Therefore, the proportion of patients initiating treatment was 31.0% in Swiss cohort study [9], and 33.0% in Danish cohort study [10].

According to Falck-Ytter et al. [4], 72% of chronic hepatitis C patients were not treated. Of these, 37% did not adhere to medical recommendations, 34% were medically or psychologically ineligible, 13% had ongoing alcohol or drug abuse, and 11% refused treatment. Only 28% of chronic hepatitis C patients were treated and 13% had a sustained viral response. Narasimhan et al. [11] retrospectively reviewed the charts of all HCV patients who underwent liver biopsies. About 60% were not treated with interferon-based therapy because of loss to follow-up or non-compliance (31%), patient preference (22%), etc. In other words, chronic hepatitis C treatment largely depended on patients’ intention to treat, not medical decisions made by doctors. Restrepo et al. [12] reported that approximately 85% of patients co-infected with HCV and human immunodeficiency virus were not treated. Of these, 40% were noncompliant with medical schedules, 15% were actively abusing drugs or alcohol, and 15% refused antiviral treatment.

In our study, 876 patients were diagnosed with chronic hepatitis C having positive results for both anti-HCV and HCV RNA. Of the 876 patients, 244 were eligible for interferon, but 39 (16%) diagnosed with HCV relapse. 632 patients could not be treated appropriately with interferon-based antiviral therapy (Fig. 1). The reasons for stopping or not receiving interferon-based antiviral treatment include malignancy (30%), co-morbidity (23%), interferon-related reasons (15%) and non-adherence (26%).

The most prevalent malignancy in our cohort was HCC (81%) (Table 2). In the interferon era, HCC was a relative contraindication for antiviral therapy; however, treating chronic hepatitis C with interferon was considered to reduce HCC recurrence and improve survival [13]. The recent introduction of DAA has been expected to reduce the incidence of HCC in HCV-related cirrhotic livers. Unfortunately, DAA-induced clearance of HCV was not able to reduce the occurrence of HCC in patients with HCV-related cirrhotic livers [14]. In spite of DAA treatment, high rate of early HCC recurrence was noted in patients previously treated for HCC [14,15]. Therefore DAA therapy in HCC patients has yet to be determined.

Patients with severe co-morbidities could not be treated with interferon-based therapy because of possible severe adverse effects. About 49% of patients had advanced or decompensated liver cirrhosis that was a contraindication to interferon therapy (Fig. 4). However, an oral DAA regimen could be safe and highly effective in treating patients who are ineligible for interferon-based antiviral therapy due to HCV-related cirrhosis, decompensation. In addition to advanced liver diseases, DAA could be administered safely in patients with symptomatic cardiovascular disease, chronic renal disease, uncontrolled diabetes, extra-hepatic transplantation and psychiatric disorders [16].

Non-adherence, financial problems and alcohol abuse are also reasons to prevent antiviral therapy. With short treatment duration and all oral regimens, improved compliance is expected in patients using DAA. On the other hand, DAA is so expensive that it would be difficult for a physician to prescribe to all chronic hepatitis C patients. Therefore, a part of compliance and socioeconomic problems would be remained in DAA era.

Therefore, we could suppose that at least 42% of patients who were ineligible or failed to interferon-based antiviral therapy due to co-morbidity (22%), interferon intolerability (14%) and HCV relapse (6%) would be treated with DAAs. However, a large portion of patients who were non-adherent (25%), had alcohol abuse (2%), or had financial concerns (2%) would not be able to get a chance to use the DAA (Fig. 5). Unlike hepatitis B virus-related HCC, patients with HCC occurred with HCV (23%, 156/671) have not been determined to be treated with DAA. This study has some limitations, including a retrospective design and that it was conducted in a single, tertiary hospital. The combined co-morbidity and malignancy rates were higher than in other Korean studies [7,17]. Therefore, the results cannot be accepted generally. In spite of the limitation, this study has a clear message considering limitation of DAA therapy in chronic hepatitis C patients who were ineligible or failed to interferon based antiviral therapy.

In conclusion, only 27.7% of patients diagnosed with chronic hepatitis C in our study were treated with an interferon-based regimen. With the advent of DAAs, at least 42% of patients who were ineligible or failed to interferon and experienced HCV relapse would be able to use DAA. However nonmedical reasons, including noncompliance, financial problems, substance abuse and hepatocelluar carcinoma remain obstacles to treat chronic hepatitis C. Our study suggests that, in spite of DAA development, eradicating HCV would be difficult due to various unexpected reasons.

HCV Education
Review learning activities, editorials, with new data about interferon-free regimens approved for HCV, as well as investigational drugs still in the pipeline. Links are provided to support, patient friendly information, clinical trials, peer-reviewed journals, videos, conferences with commentary, all updated on a continuous basis.

Users can search for a hepatitis C clinical trial by category (genotype), or learn how to evaluate a clinical trial and become familiar with commonly used terms. HCV Advocate offers an easy to navigate HCV Medications Blog as well, organized by HCV genotype

View each rebuttal and all ongoing media coverage. In June the HCV community was blindsided when an article with a somewhat "clickbait" headline was released by The Guardian. The Guardian reported on a systematic review published by the Cochrane Collaboration that suggested achieving SVR (cure) for patients using hepatitis C direct-acting antivirals (DAAs) doesn't correlate with any long term benefits.

The controversy over expensive new drugs for hepatitis C
Link to research and news articles addressing the high cost of hepatitis C drugs; insurance restrictions - private insurers/Medicaid - and availability of generic versions/India, Egypt and other lower-income countries or through online "buyers clubs"

Liver Cancer After Treatment For Hepatitis C
​Research demonstrates that while SVR markedly reduced liver-related complications and liver cancer, some long-term risk for liver cancer remained in those who were cured of Hepatitis C. But after direct-acting antiviral therapy does the risk of developing liver cancer increase?

Meeting Updates

April 19-23
The European Association for the Study of the Liver (EASL) International Liver Congress (ILC 2017)

Merck today announced its strategic decision to discontinue the development of the investigational combination regimens MK-3682B (grazoprevir/ruzasvir/ uprifosbuvir) and MK-3682C (ruzasvir/uprifosbuvir) for the treatment of chronic hepatitis C virus (HCV) infection. This decision was made based on a review of available Phase 2 efficacy data and in consideration of the evolving marketplace and the growing number of treatment options available for patients with chronic HCV infection

Two HCV Drugs to Be Discontinued
The Food and Drug Administration (FDA) announced that Rebetol(ribavirin; Merck) capsules and PegIntron (peginterferon alfa-2b; Merck) for Injection are being discontinued. The decision is business-related and not due to safety or efficacy issues with the drugs.

Rebetol is a nucleoside analogue indicated for chronic hepatitis C in combination with interferon alfa-2b (pegylated and nonpegylated), in patients ≥3 years of age with compensated liver disease. It is supplied as 200mg capsules in 56-, 70-, and 84-count bottles. The Rebetol discontinuation is effective February 1, 2016.
PegIntron is an antiviral indicated for treatment of chronic hepatitis C in patients with compensated liver disease. It is supplied as 50mcg/0.5mL, 80mcg/0.5mL, 120mcg/0.5mL, and 150mcg/0.5mL single-use vials and single-use pre-filled pens. No effective date is available for the PegIntron discontinuation.

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